Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial

BMC Psychiatry

Miranda Olff²  Dick J Veltman¹  Damiaan Denys⁴  Fred C Bakker⁶  Adriaan Honig¹  Tessa H Biesheuvel⁶  Jan S Luitse⁵  J Carel Goslings⁵  Laura Nawijn³  Saskia BJ Koch³  Mirjam van Zuiden³  Jessie L Frijling³ 

[1] Department of Psychiatry, VU University Medical Center, Amsterdam, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands;Arq Psychotrauma Expert Group, Nienoord 5, Diemen 1112 XE, Netherlands;Department of Psychiatry, Academic Medical Center, University of Amsterdam, Meibergdreef 5, 1105 AZ Amsterdam, The Netherlands;Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands;Trauma Unit, Department of Surgery, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands;Department of Surgery, VU University Medical Center, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands

关键词: Prevention;    Randomized controlled trial;    Neurobiology;    Oxytocin;    Early intervention;    PTSD;    Post-traumatic disorder;   

Others  :  1123679
DOI  :  10.1186/1471-244X-14-92

 received in 2013-08-30, accepted in 2014-03-18,  发布年份 2014

【 摘 要 】

Background

Currently few evidence based interventions are available for the prevention of PTSD within the first weeks after trauma. Increased risk for PTSD development is associated with dysregulated fear and stress responses prior to and shortly after trauma, as well as with a lack of perceived social support early after trauma. Oxytocin is a potent regulator of these processes. Therefore, we propose that oxytocin may be important in reducing adverse consequences of trauma. The ‘BONDS’ study is conducted in order to assess the efficacy of an early intervention with intranasal oxytocin for the prevention of PTSD.

Methods/Design

In this multicenter double-blind randomized placebo-controlled trial we will recruit 220 Emergency Department patients at increased risk of PTSD. Trauma-exposed patients are screened for increased PTSD risk with questionnaires assessing peri-traumatic distress and acute PTSD symptoms within 7 days after trauma. Baseline PTSD symptom severity scores and neuroendocrine and psychophysiological measures will be collected within 10 days after trauma. Participants will be randomized to 7.5 days of intranasal oxytocin (40 IU) or placebo twice a day. Follow-up measurements at 1.5, 3 and 6 months post-trauma are collected to assess PTSD symptom severity (the primary outcome measure). Other measures of symptoms of psychopathology, and neuroendocrine and psychophysiological disorders are secondary outcome measures.

Discussion

We hypothesize that intranasal oxytocin administered early after trauma is an effective pharmacological strategy to prevent PTSD in individuals at increased risk, which is both safe and easily applicable. Interindividual and contextual factors that may influence the effects of oxytocin treatment will be considered in the analysis of the results.

Trial registration

Netherlands Trial Registry: NTR3190.

【 授权许可】

   
2014 Frijling et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]de Vries GJ, Olff M: The lifetime prevalence of traumatic events and posttraumatic stress disorder in the Netherlands. J Trauma Stress 2009, 22(4):259-267.
• [2]Frans O, Rimmo PA, Aberg L, Fredrikson M: Trauma exposure and post-traumatic stress disorder in the general population. Acta Psychiatr Scand 2005, 111(4):291-299.
• [3]Resnick HS, Kilpatrick DG, Dansky BS, Saunders BE, Best CL: Prevalence of civilian trauma and posttraumatic stress disorder in a representative national sample of women. J Consult Clin Psychol 1993, 61(6):984-991.
• [4]Breslau N, Kessler RC, Chilcoat HD, Schultz LR, Davis GC, Andreski P: Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma. Arch Gen Psychiatry 1998, 55(7):626-632.
• [5]Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU: Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res 2012, 21(3):169-184.
• [6]Management of Post-Traumatic Stress Working Group: VA/DoD clinical practice guideline for management of post-traumatic stress. Washington, DC: Veterans Health Administration, Department of Defense; 2010.
• [7]Sijbrandij M, Olff M, Reitsma JB, Carlier IV, Gersons BP: Emotional or educational debriefing after psychological trauma. Randomised controlled trial. Br J Psychiatry 2006, 189:150-155.
• [8]Rose S, Bisson J, Wessely S: A systematic review of single-session psychological interventions (‘debriefing’) following trauma. Psychother Psychosom 2003, 72(4):176-184.
• [9]Roberts NP, Kitchiner NJ, Kenardy J, Bisson JI: Systematic review and meta-analysis of multiple-session early interventions following traumatic events. Am J Psychiatry 2009, 166(0002–953; 3):293-301.
• [10]Rothbaum BO, Kearns MC, Price M, Malcoun E, Davis M, Ressler KJ, Lang D, Houry D: Early intervention may prevent the development of posttraumatic stress disorder: a randomized pilot civilian study with modified prolonged exposure. Biol Psychiatry 2012, 72(11):957-963.
• [11]Bisson JI, Shepherd JP, Joy D, Probert R, Newcombe RG: Early cognitive-behavioural therapy for post-traumatic stress symptoms after physical injury. Randomised controlled trial. Br J Psychiatry 2004, 184:63-69.
• [12]Sijbrandij M, Olff M, Reitsma JB, Carlier IV, de Vries MH, Gersons BP: Treatment of acute posttraumatic stress disorder with brief cognitive behavioral therapy: a randomized controlled trial. Am J Psychiatry 2007, 164(0002–953; 0002–953; 1):82-90.
• [13]Hoge EA, Worthington JJ, Nagurney JT, Chang Y, Kay EB, Feterowski CM, Katzman AR, Goetz JM, Rosasco ML, Lasko NB, Zusman RM, Pollack MH, Orr SP, Pitman RK: Effect of acute posttrauma propranolol on PTSD outcome and physiological responses during script-driven imagery. CNS Neurosci Ther 2012, 18(1):21-27.
• [14]Stein MB, Kerridge C, Dimsdale JE, Hoyt DB: Pharmacotherapy to prevent PTSD: Results from a randomized controlled proof-of-concept trial in physically injured patients. J Trauma Stress 2007, 20(6):923-932.
• [15]Zohar J, Yahalom H, Kozlovsky N, Cwikel-Hamzany S, Matar MA, Kaplan Z, Yehuda R, Cohen H: High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies. Eur Neuropsychopharmacol 2011, 21(11):796-809.
• [16]Delahanty DL, Gabert-Quillen C, Ostrowski SA, Nugent NR, Fischer B, Morris A, Pitman RK, Bon J, Fallon W: The efficacy of initial hydrocortisone administration at preventing posttraumatic distress in adult trauma patients: a randomized trial. CNS Spectr 2013, 18(2):103-111.
• [17]Shaikh al Arab A, Guedon-Moreau L, Ducrocq F, Molenda S, Duhem S, Salleron J, Chaudieu I, Bert D, Libersa C, Vaiva G: Temporal analysis of heart rate variability as a predictor of post traumatic stress disorder in road traffic accidents survivors. J Psychiatr Res 2012, 46(6):790-796.
• [18]Apfel BA, Otte C, Inslicht SS, McCaslin SE, Henn-Haase C, Metzler TJ, Makotkine I, Yehuda R, Neylan TC, Marmar CR: Pretraumatic prolonged elevation of salivary MHPG predicts peritraumatic distress and symptoms of post-traumatic stress disorder. J Psychiatr Res 2011, 45(6):735-741.
• [19]Van Zuiden M, Kavelaars A, Geuze E, Olff M, Heijnen CJ: Predicting PTSD: pre-existing vulnerabilities in glucocorticoid-signaling and implications for preventive interventions. Brain Behav Immun 2013, 30:12-21.
• [20]Van Zuiden M, Geuze E, Willemen HL, Vermetten E, Maas M, Amarouchi K, Kavelaars A, Heijnen CJ: Glucocorticoid receptor pathway components predict Posttraumatic Stress Disorder symptom development: a prospective study. Biol Psychiatry 2011, 71(4):309-316.
• [21]McFarlane AC, Barton CA, Yehuda R, Wittert G: Cortisol response to acute trauma and risk of posttraumatic stress disorder. Psychoneuroendocrinology 2011, 36(5):720-727.
• [22]Admon R, Lubin G, Rosenblatt JD, Stern O, Kahn I, Assaf M, Hendler T: Imbalanced neural responsivity to risk and reward indicates stress vulnerability in humans. Cereb Cortex 2013, 23(1):28-35.
• [23]Qin L, Wang Z, Sun Y, Wan J, Su S, Zhou Y, Xu J: A preliminary study of alterations in default network connectivity in post-traumatic stress disorder patients following recent trauma. Brain Res 2012, 1484:50-56.
• [24]Zhou Y, Wang Z, Wan J, Sun Y, Su S, Ding W, Xu J: Early altered resting-state functional connectivity predicts the severity of post-traumatic stress disorder symptoms in acutely traumatized subjects. PLoS One 2012, 7(10):e46833.
• [25]Brewin CR, Andrews B, Valentine JD: Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults. J Consult Clin Psychol 2000, 68(5):748-766.
• [26]Ozer EJ, Best SR, Lipsey TL, Weiss DS: Predictors of posttraumatic stress disorder and symptoms in adults: a meta-analysis. Psychol Bull 2003, 129(1):52-73.
• [27]Robinaugh DJ, Marques L, Traeger LN, Marks EH, Sung SC, Gayle BJ, Pollack MH, Simon NM: Understanding the relationship of perceived social support to post-trauma cognitions and posttraumatic stress disorder. J Anxiety Disord 2011, 25(8):1072-1078.
• [28]Olff M: Bonding after trauma: on the role of social support and the oxytocin system in traumatic stress. Eur J Psychotraumatol 2012., 3doi:10.3402/ejpt.v3i0.18597
• [29]Gautvik KM, de Lecea L, Gautvik VT, Danielson PE, Tranque P, Dopazo A, Bloom FE, Sutcliffe JG: Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction. Proc Natl Acad Sci U S A 1996, 93(16):8733-8738.
• [30]Williams JR, Carter CS, Insel T: Partner preference development in female prairie voles is facilitated by mating or the central infusion of oxytocin. Ann N Y Acad Sci 1992, 652(1):487-489.
• [31]Carter CS, Williams JR, Witt DM, Insel TR: Oxytocin and social bonding. Ann N Y Acad Sci 1992, 652(1):204-211.
• [32]Holt-Lunstad J, Birmingham WA, Light KC: Influence of a “warm touch” support enhancement intervention among married couples on ambulatory blood pressure, oxytocin, alpha amylase, and cortisol. Psychosom Med 2008, 70(9):976-985.
• [33]Seltzer LJ, Ziegler TE, Pollak SD: Social vocalizations can release oxytocin in humans. Proc Biol Sci 2010, 277(1694):2661-2666.
• [34]Tops M, van Peer JM, Korf J, Wijers AA, Tucker DM: Anxiety, cortisol, and attachment predict plasma oxytocin. Psychophysiology 2007, 44(3):444-449.
• [35]Turner RA, Altemus M, Enos T, Cooper B, McGuinness T: Preliminary research on plasma oxytocin in normal cycling women: investigating emotion and interpersonal distress. Psychiatry 1999, 62(2):97-113.
• [36]Altemus M, Deuster PA, Galliven E, Carter CS, Gold PW: Suppression of hypothalmic-pituitary-adrenal axis responses to stress in lactating women. J Clin Endocrinol Metab 1995, 80(10):2954-2959.
• [37]Light KC, Grewen KM, Amico JA: More frequent partner hugs and higher oxytocin levels are linked to lower blood pressure and heart rate in premenopausal women. Biol Psychol 2005, 69(1):5-21.
• [38]Weisman O, Zagoory-Sharon O, Feldman R: Intranasal oxytocin administration is reflected in human saliva. Psychoneuroendocrinology 2012, 37(9):1582-1586.
• [39]Van Ijzendoorn MH, Bhandari R, van der Veen R, Grewen KM, Bakermans-Kranenburg MJ: Elevated salivary levels of oxytocin persist more than 7 h after intranasal administration. Front Neurosci 2012, 6:174.
• [40]Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E: Oxytocin increases trust in humans. Nature 2005, 435(7042):673-676.
• [41]Van Ijzendoorn MH, Bakermans-Kranenburg MJ: A sniff of trust: meta-analysis of the effects of intranasal oxytocin administration on face recognition, trust to in-group, and trust to out-group. Psychoneuroendocrinology 2012, 37(3):438-443.
• [42]Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U: Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 2003, 54(12):1389-1398.
• [43]Norman GJ, Cacioppo JT, Morris JS, Malarkey WB, Berntson GG, DeVries AC: Oxytocin increases autonomic cardiac control: Moderation by loneliness. Biol Psychol 2011, 86(3):174-180.
• [44]Domes G, Heinrichs M, Glascher J, Buchel C, Braus DF, Herpertz SC: Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry 2007, 62(10):1187-1190.
• [45]Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, Gruppe H, Mattay VS, Gallhofer B, Meyer-Lindenberg A: Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 2005, 25(49):11489-11493.
• [46]Singer T, Snozzi R, Bird G, Petrovic P, Silani G, Heinrichs M, Dolan RJ: Effects of oxytocin and prosocial behavior on brain responses to direct and vicariously experienced pain. Emotion 2008, 8(6):781-791.
• [47]Sripada CS, Phan KL, Labuschagne I, Welsh R, Nathan PJ, Wood AG: Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex. Int J Neuropsychopharmacol 2012, 16(02):255-260.
• [48]Kubzansky LD, Mendes WB, Appleton AA, Block J, Adler GK: A heartfelt response: oxytocin effects on response to social stress in men and women. Biol Psychol 2012, 90(1):1-9.
• [49]De Dreu CK: Oxytocin modulates the link between adult attachment and cooperation through reduced betrayal aversion. Psychoneuroendocrinology 2012, 37(7):871-880.
• [50]Riem MM, van Ijzendoorn MH, Tops M, Boksem MA, Rombouts SA, Bakermans-Kranenburg MJ: Oxytocin effects on complex brain networks are moderated by experiences of maternal love withdrawal. Eur Neuropsychopharmacol 2013, 23(10):1288-1295.
• [51]Bartz JA, Zaki J, Bolger N, Ochsner KN: Social effects of oxytocin in humans: context and person matter. Trends Cogn Sci 2011, 15(7):301-309.
• [52]Olff M, Frijling JL, Kubzansky LD, Bradley B, Ellenbogen MA, Cardoso C, Bartz JA, Yee JR, van Zuiden M: The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences. Psychoneuroendocrinology 2013, 38(9):1883-1894.
• [53]Cohen H, Kaplan Z, Kozlovsky N, Gidron Y, Matar MA, Zohar J: Hippocampal microinfusion of oxytocin attenuates the behavioural response to stress by means of dynamic interplay with the glucocorticoid-catecholamine responses. J Neuroendocrinol 2010, 22(8):889-904.
• [54]Toth I, Neumann ID, Slattery DA: Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner. Psychopharmacology (Berl) 2012, 223(2):149-158.
• [55]Yatzkar U, Klein E: Intranasal oxytocin in patients with post traumatic stress disorder: a single dose, pilot double blind crossover study. Clin Neuropsychopharmacol 2009, 20:S84-S84.
• [56]Brewin CR, Rose S, Andrews B, Green J, Tata P, McEvedy C, Turner S, Foa EB: Brief screening instrument for post-traumatic stress disorder. Br J Psychiatry 2002, 181:158-162.
• [57]Brunet A, Weiss DS, Metzler TJ, Best SR, Neylan TC, Rogers C, Fagan J, Marmar CR: The peritraumatic distress inventory: a proposed measure of PTSD criterion A2. Am J Psychiatry 2001, 158(9):1480-1485.
• [58]Walters JT, Bisson JI, Shepherd JP: Predicting post-traumatic stress disorder: validation of the Trauma Screening Questionnaire in victims of assault. Psychol Med 2007, 37(1):143-150.
• [59]Nishi D, Matsuoka Y, Yonemoto N, Noguchi H, Kim Y, Kanba S: Peritraumatic distress inventory as a predictor of post-traumatic stress disorder after a severe motor vehicle accident. Psychiatry Clin Neurosci 2010, 64(2):149-156.
• [60]Mouthaan J, Sijbrandij M, Reitsma JB, Gersons BPR, Olff M: Early screening for posttraumatic stress disorder: a comparative accuracy study. in preparation
• [61]Feifel D, Macdonald K, Nguyen A, Cobb P, Warlan H, Galangue B, Minassian A, Becker O, Cooper J, Perry W, Lefebvre M, Gonzales J, Hadley A: Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients. Biol Psychiatry 2010, 68(7):678-680.
• [62]Ohlsson B, Truedsson M, Bengtsson M, Torstenson R, Sjolund K, Bjornsson ES, Simren M: Effects of long-term treatment with oxytocin in chronic constipation; a double blind, placebo-controlled pilot trial. Neurogastroenterol Motil 2005, 17(5):697-704.
• [63]Macdonald E, Dadds MR, Brennan JL, Williams K, Levy F, Cauchi AJ: A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology 2011, 36(8):1114-1126.
• [64]Foa EB, Riggs DS, Dancu CV, Rothbaum BO: Reliability and validity of a brief instrument for assessing post-traumatic stress disorder. J Trauma Stress 1993, 6(4):459-473.
• [65]American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (fourth ed., text revision). Washington, DC: Author; 2000.
• [66]Dekkers AM, Olff M, Naring GW: Identifying persons at risk for PTSD after trauma with TSQ in the Netherlands. Community Ment Health J 2010, 46(1):20-25.
• [67]Jehel L, Brunet A, Paterniti S, Guelfi JD: Validation of the peritraumatic distress inventory’s French translation. Can J Psychiatry 2005, 50(1):67-71.
• [68]Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, Keane TM: The development of a Clinician-Administered PTSD Scale. J Trauma Stress 1995, 8(1):75-90.
• [69]Hovens JE, van DP, Klaarenbeek MT, Bramsen I, Schreuder JN, Rivero VV: The assessment of posttraumatic stress disorder: with the Clinician Administered PTSD Scale: Dutch results. J Clin Psychol 1994, 50(3):325-340.
• [70]Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC: The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998, 59(20):22-33.
• [71]Van Vliet IM, De Beurs E: [The MINI-International Neuropsychiatric Interview. A brief structured diagnostic psychiatric interview for DSM-IV en ICD-10 psychiatric disorders]. Tijdschr Psychiatr 2007, 46(6):393-397.
• [72]Zigmond AS, Snaith RP: The hospital anxiety and depression scale. Acta Psychiatr Scand 1983, 67(0001–690; 0001–690; 6):361-370.
• [73]Spinhoven P, Ormel J, Sloekers PP, Kempen GI, Speckens AE, Van Hemert AM: A validation study of the Hospital Anxiety and Depression Scale (HADS) in different groups of Dutch subjects. Psychol Med 1997, 27(2):363-370.
• [74]Weiss DS: The impact of event scale-revised. In Assessing Psychological Trauma and PTSD. 2nd edition. Edited by Wilson JP, Keane TM. New York, NY: Guilford Press; 2004:168-169.
• [75]Vercoulen JHMM, Alberts M, Bleijenberg G: The checklist individual strength. Gedragstherapie 1999, 32:131-136.
• [76]Eriksen HR, Ihlebaek C, Ursin H: A scoring system for subjective health complaints (SHC). Scand J Public Health 1999, 27(1):63-72.
• [77]Skevington SM, Lotfy M, O’Connell KA: The World Health Organization’s WHOQOL-BREF quality of life assessment: psychometric properties and results of the international field trial. A report from the WHOQOL group. Qual Life Res 2004, 13(2):299-310.
• [78]Trompenaars FJ, Masthoff ED, Van Heck GL, Hodiamont PP, De Vries J: Content validity, construct validity, and reliability of the WHOQOL-Bref in a population of Dutch adult psychiatric outpatients. Qual Life Res 2005, 14(1):151-160.
• [79]Spielberger CD, Gorsuch RL, Lushene RE: Manual for the state-trait anxiety inventory. Palo Alto, CA: Consulting Psychologists Press; 1970.
• [80]Van der Ploeg H: Validity of the zelf-beoordelings-vragenlijst (a Dutch version of the spielberger state-trait anxiety inventory). Ned Tijdschr Psychol 1980, 35(4):243-249.
• [81]Van Sonderen E: Sociale steun lijst-interacties (SSL-I) en sociale steun lijst-discrepanties (SSL-D): een handleiding [social support list-interactions (SSL-I) and social support list-discripancies (SSL-D): a manual]. Groningen: Noordelijk Centrum voor Gezondheidsvraagstukken, Rijksuniversiteit Groningen; 1993.
• [82]Brennan KA, Clark CL, Shaver PR: Self-report measurement of adult attachment. In Attachment Theory and Close Relationships. Edited by Simpsom JA, Rholes WS. New York: The Guilford Press; 1998:46-76.
• [83]Ravitz P, Maunder R, Hunter J, Sthankiya B, Lancee W: Adult attachment measures: a 25-year review. J Psychosom Res 2010, 69(4):419-432.
• [84]Amirkhan JH: Criterion validity of a coping measure. J Pers Assess 1994, 62(2):242-261.
• [85]Marmar CR, Metzler TJ, Otte C: The peritraumatic dissociative experiences questionnaire. In Assessing Psychological Trauma and PTSD. 2nd edition. Edited by Wilson JP, Keane TM. New York, NY: Guilford Press; 2004:144-167.
• [86]Sijbrandij M, Engelhard IM, Opmeer BC, van de Schoot R, Carlier IV, Gersons BP, Olff M: The structure of peritraumatic dissociation: a cross validation in clinical and nonclinical samples. J Trauma Stress 2012, 25(4):475-479.
• [87]Bremner JD, Vermetten E, Mazure CM: Development and preliminary psychometric properties of an instrument for the measurement of childhood trauma: the Early Trauma Inventory. Depress Anxiety 2000, 12(1):1-12.
• [88]Quintana DS, Heathers JA, Kemp AH: On the validity of using the Polar RS800 heart rate monitor for heart rate variability research. Eur J Appl Physiol 2012, 112:4179-4180.
• [89]Griffin MG, Resick PA, Yehuda R: Enhanced cortisol suppression following dexamethasone administration in domestic violence survivors. Am J Psychiatry 2005, 162(6):1192.
• [90]Gow R, Thomson S, Rieder M, Van Uum S, Koren G: An assessment of cortisol analysis in hair and its clinical applications. Forensic Sci Int 2010, 196(1):32-37.
• [91]Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ: Epigenetic programming by maternal behavior. Nat Neurosci 2004, 7(8):847-854.
• [92]Szyf M: The early life social environment and DNA methylation: DNA methylation mediating the long-term impact of social environments early in life. Epigenetics 2011, 6(8):971-978.
• [93]Smith AK, Conneely KN, Kilaru V, Mercer KB, Weiss TE, Bradley B, Tang Y, Gillespie CF, Cubells JF, Ressler KJ: Differential immune system DNA methylation and cytokine regulation in post‒traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet 2011, 156(6):700-708.
• [94]Roth TL, Lubin FD, Funk AJ, Sweatt JD: Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 2009, 65(9):760-769.
• [95]Uddin M, Aiello AE, Wildman DE, Koenen KC, Pawelec G, de Los SR, Goldmann E, Galea S: Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc Natl Acad Sci U S A 2010, 107(20):9470-9475.
• [96]Elashoff JD: nQuery Advisor (Version 7.0) [Computer software]. Boston, MA: Statistical Solutions; 2007.
• [97]Pedersen CA, Gibson CM, Rau SW, Salimi K, Smedley KL, Casey RL, Leserman J, Jarskog LF, Penn DL: Intranasal oxytocin reduces psychotic symptoms and improves theory of mind and social perception in schizophrenia. Schizophr Res 2011, 132(1):50-53.
• [98]Mouthaan J, Sijbrandij M, de Vries GJ, Reitsma JB, van de Schoot R, Goslings JC, Luitse JS, Bakker FC, Gersons BP, Olff M: Internet-based early intervention to prevent posttraumatic stress disorder in injury patients: randomized controlled trial. J Med Internet Res 2013, 15(8):e165.
• [99]Bryant RA, O’Donnell ML, Creamer M, McFarlane AC, Clark CR, Silove D: The psychiatric sequelae of traumatic injury. Am J Psychiatry 2010, 167(3):312-320.
• [100]Delahanty DL, Raimonde AJ, Spoonster E, Cullado M: Injury severity, prior trauma history, urinary cortisol levels, and acute PTSD in motor vehicle accident victims. J Anxiety Disord 2003, 17(2):149-164.
• [101]Kearns MC, Ressler KJ, Zatzick D, Rothbaum BO: Early interventions for PTSD: a review. Depress Anxiety 2012, 29(10):833-842.
• [102]Van Zuiden M, Heijnen CJ, Maas M, Amarouchi K, Vermetten E, Geuze E, Kavelaars A: Glucocorticoid sensitivity of leukocytes predicts PTSD, depressive and fatigue symptoms after military deployment: a prospective study. Psychoneuroendocrinology 2012, 37(11):1822-1836.
• [103]Goldman MB, Gomes AM, Carter CS, Lee R: Divergent effects of two different doses of intranasal oxytocin on facial affect discrimination in schizophrenic patients with and without polydipsia. Psychopharmacology (Berl) 2011, 216(1):101-110.
• [104]Cardoso C, Ellenbogen MA, Orlando MA, Bacon SL, Joober R: Intranasal oxytocin attenuates the cortisol response to physical stress: a dose–response study. Psychoneuroendocrinology 2012, 38(3):399-407.
• [105]Hall SS, Lightbody AA, McCarthy BE, Parker KJ, Reiss AL: Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome. Psychoneuroendocrinology 2012, 37(4):509-518.
• [106]Guastella AJ, Hickie IB, McGuinness MM, Otis M, Woods EA, Disinger HM, Chan H, Chen TF, Banati RB: Recommendations for the standardisation of oxytocin nasal administration and guidelines for its reporting in human research. Psychoneuroendocrinology 2013, 38(5):612-625.